1. Field of the Invention
This invention relates to a method of preventing or ameliorating acute renal failure in mammals The acute renal failure may be due to reduced renal blood flow or nephrotoxins leading to cell necrosis and reduced kidney function.
2. Description of Related Art
Insulin-like growth factor I (IGF-I) is a polypeptide naturally occurring in human body fluids, for example, blood and human cerebral spinal fluid. Most tissues, including the kidney, produce IGF-I together with specific IGF-binding proteins. IGF-I production is under the dominant stimulatory influence of growth hormone (GH), and some of the IGF-I binding proteins are also influenced by GH. See Tanner et al., Acta Endocrinol., 84: 681-696 (1977); Uthne et al., J. Clin. Endocrinol. Metab., 39: 548-554 (1974). IGF-I has been isolated from human serum and produced recombinantly. See, e.g., EP 123,228 and 128,733.
Human growth hormone (hGH) is a single-chain polypeptide consisting of 191 amino acids (molecular weight 21,500). Disulfide bonds link positions 53 and 165 and positions 182 and 189. Niall, Nature, New Biology. 230: 90 (1971). hGH is a potent anabolic agent, especially due to retention of nitrogen, phosphorus, potassium, and calcium. Treatment of hypophysectomized rats with GH can restore at least a portion of the growth rate of the rats. Moore et al., Endocrinology, 122: 2920.2926 (1988). Among its most striking effects in hypopituitary (GH-deficient) subjects is accelerated linear growth of bone growth plate cartilage resulting in increased stature. Kaplan, Growth Disorders in Children and Adolescents (Springfield, Ill.: Charles C. Thomas, 1964).
It has been reported that, especially in women after menopause, GH secretion declines with age. Millard et al., Neurobiol. Aging, 229-235 (1990); Takahashi et al., Neuroendocrinology, 46: 137-142 (1987). See also Rudman et al., J. Clin. Invest., 67: 1361-1369 (1981) and Blackman, Endocrinology and Aging, 16: 981 (1987). Moreover, a report exists that some of the manifestations of aging, including decreased lean body mass, expansion of adipose-tissue mass, and the thinning of the skin, can be reduced by GH treatment three times a week. See, e.g., Rudman et al., N. Eng. J. Med., 323: 1-6 (1990) and the accompanying article in the same journal issue by Dr. Vance (pp. 52-54).
The levels of IGF-I are reported to be reduced by half in 20-month old rats compared to 6-month old rats. Takahashi and Meiters, Proc. Soc. Exp. Biol. Med., 186: 229-233 (1987). See also Florini and Roberts, J. Gerontol., 35: 23-30 (1980); Florini et al., Mech. Ageing Dev., 15: 165-176 (1981); Chatelain et al., Pediatrie, 44: 303-308 (1989); Florini et al., J. Gerontol., 40: 2-7 (1985); Hall and Sara, Clinics in Endocrin, and Metab., 13: 91 (1984); Baxter, Advances in Clinical Chemistry, 25: 49 (1986); Clemmons and Underwood, Clinics in Endocrin. and Metab. 15: 629 (1986); Hintz, Advances in Pediatrics, 28: 293 (Year Book Medical Publishers, Inc., 1981); Johanson and Blizzard, The Johns Hopkins Medical Journal, 149: 115-117 (1981), the latter five references describing low IGF-I levels in aged men. The Hintz, Clemmons and Underwood, and Baxter references are general reviews on IGF-I.
Furthermore, it was found that among human diploid fibroblasts capable of cycling in aging cultures in vitro, there were few changes in the regulation of the growth fraction by platelet-derived growth factor (PDGF) and epidermal growth factor (EGF), but a greatly increased dependence on IGF-I for regulation of the rate of entry into S phase. Chen and Rabinovitch, J. Cell. Physiol., 144: 18-25 (1990). The authors conclude that the slower growth of the dividing population of cells in aging cultures may be related to a requirement for IGF-I at levels that are greatly above those usually supplied This may be due to overproduction of the IGF-I binding protein, IGFBP-3, and, therefore, a reduction in IGF-I availability to its receptor. Goldstein et al., "Cellular and Molecular Applications to Biology of Aging", AFCR Meeting abstract, Seattle, May 4-5, 1991.
Various biological activities of IGF-I in other than aged mammals have been identified. For example, IGF-I is reported to lower blood glucose levels in humans for use in treating diabetes Guler et al., N. Engl. J. Med., 317: 137-140 (1987); Froesch et al., U.S. Pat. No. 4,988,675. Additionally, IGF-I is reported as useful in treating cardiac disorders (WO 92/11865 published 23 Jul. 1992) and in promoting growth in several metabolic conditions characterized by low IGF-I levels, such as hypophysectomized rats (Skottner et al., J. Endocr., 112: 123-132 [1987]), diabetic rats (Scheiwiller et al., Nature, 323: 169-171 [1986]), and dwarf rats (Skottner et al., Endocrinology, 124: 2519-2526 [1989]). The anabolic effect of IGF-I in rapidly growing neonatal rats was demonstrated in vivo. Philipps et al., Pediatric Res., 23: 298 (1988). In underfed, stressed, ill, or diseased animals, IGF-I levels are well known to be depressed.
The kidney weight of hypophysectomized rats increases substantially upon prolonged infusions of IGF-I subcutaneously. Guler et al., Proceedings of the 1st European Congress of Endocrinology, 103: abstract 12-390 (Copenhagen, 1987); Guler et al., Proc. Natl. Acad. Sci. USA. 85: 4889-4893 (1988). The kidneys of Snell dwarf mice and dwarf rats behaved similarly. van Buul-Offers et al., Pediatr. Res., 20: 825-827 (1986); Skottner et al., Endocrinology, supra. A truncated IGF-I molecule called des-IGF-I that has the first three amino acids removed from its N-terminus was found to be more potent than IGF-I as a kidney growth factor in GH-deficient rats. Lemmey et al., Am. J. Physiol., 260: E213-E219 (1991).
There is a long history of studies showing that the administration of GH to humans and animals increases glomerular filtration rate, renal plasma flow, proximal tubular phosphate reabsorption, and proximal tubular gluceoneogenesis. Corvilain and Abramow, J. Clin. Invest., 41: 1230-1235 (1962); Corvilain and Abramow, J. Clin. Invest., 43: 1608-1612 (1964). Besides these effects on kidney function, GH excess has also been reported to cause glomeruli and proximal tubules to hypertrophy (Gershberg et al., J. Clin. Endocrinol, Metab., 17: 377-385 [1957]). However, it was also recognized that some of these effects of GH were not direct, as in humans kidney function was unchanged by short-term GH infusions. Parving et al., Acta Endocrinol., 89: 796-800 [1978].
The GH-IGF axis is implicated in normal tissue growth and anabolic activity throughout the body. The actions of GH are believed to be largely mediated by the IGFs, which were originally termed "somatomedins," or mediators of growth. IGF-I levels increase in contralateral kidneys 1-2 days following unilateral nephrectomy, experimental diabetes, and potassium depletion. Flyvbjerg et al., "Kidney IGF-I Accumulation Occurs in Four Different Conditions with Rapid Initial Kidney Growth in Rats," Modern Concepts of Insulin-Like Growth Factors, EM Spencer, eds., Elsevier Publishing, N.Y., pp. 207-217 (1991); Stiles et al., Endocrinology, 117: 2397-2401 (1985). It was found that GH stimulates IGF-I gene expression in an isolated rat renal collecting duct. Rogers et al., J. Amer. Phys., F474-F479 (1990). GH can correct a striking acidification defect in hypophysectomized rat kidneys in a dose-dependent manner. Welbourne and Cronin, Amer. J. Phys., R1036-R1042 (1991).
While some of the effects previously seen with GH were subsequently seen when IGF-I was administered to animals and humans (Guler et al., Proc. Natl. Acad. Sci. USA, 85: 4889-4893 [1988]), the IGFs are not necessarily regulated by GH. Different results of the effects of GH and IGF-I on rabbit proximal convoluted tubule transport were seen by Quigley and Baum, J. Clin. Invest., 88: 368-374 (1991). In their hands, while GH had no effect on phosphate transport, IGF-I stimulated directly phosphate transport in the rabbit proximal convoluted tubule.
There were concurrent reports that the kidney produced IGFs in response to GH administration, and that IGF-I is highly concentrated in renal tissue McConaghey and Dehnel, J. Endocrinol., 52: 587-588 (1972); D'Ercole et al., Proc. Natl Acad. Sci. USA 81: 935-939 (1984). These observations were expanded subsequently to show a steady-state level of IGF-I mRNA in the kidney even in the absence of GH (Murphy et al., Endocrinology, 121: 684-691 [1987]) and the localization by immunohistochemistry of IGF-I peptide to kidney collecting ducts. Andersson and Jennische, Acta Physiol. Scand., 132: 453-457 (1988). Also, IGF-I mRNA has been identified in the collecting duct of rat kidneys (Fagin and Melmed, Endocrinol., 120: 718-723 [1987]) and in the human fetus. Han et al., Science Wash. EDC, 236: 193-198 (1987); Han et al., Pediatrics Res., 22: 245-247 (1987). Further, the efficacy of IGF-I on kidney growth was not reduced by concurrent GH administration. U.S. Pat. No. 5,126,324 issued Jun. 30, 1992.
In the kidney IGF-I mRNA is produced both autonomously and by GH binding to receptors in the collecting ducts, which increases IGF-I mRNA. The IGF-I produced then enters the extracellular space to interact in a paracrine fashion with IGF-I receptors in the proximal tubule. GH was found to stimulate IGF-I gene expression in an isolated rat renal collecting duct. Rogers et al., Am. J. Physiol., 259: F474-F479 [1990]. Renal tissue is very responsive to IGF-I due to high concentrations of IGF-I receptors on membranes of the renal cells. Hammerman, Am J. Physiol., 257: F503-F514 (1989); Rogers and Hammerman, Proc. Natl. Acad. Sci. USA. 86: 6363-6366 (1989); Hammerman and Gavin, Am. J. Physiol., 251: E32-E41 (1986): Pillion et al., Am. J. Physiol., 255: E504-E512 (1988): Hammerman and Rogers, Am. J. Physiol., 253: F841-F847 (1987). IGF-I receptors are also located in the arterial smooth muscle, vascular endothelium, and basolateral membrane. Conti et al., Am J. Physiol., 255: F1214-F1219 (1988); Arnqvist et al., Am J. Physiol., 254: C411-C414 (1988).
Elevated circulating GH is associated with increased renal plasma flow and glomerular renal flow. Indeed, measures of renal hemodynamics rise within several hours after a single injection of GH, at about the same time that serum IGF-I concentrations increase. These findings suggested that IGF-I may increase renal plasma flow and glomerular filtration rate. In fact, IGF-I was found to increase glomerular filtration and renal plasma flow (Guler et al., Proc. Natl. Acad. Sci. USA, 86: 2868-2872 [1989]), and to stimulate renal phosphate transport and plasma 1,25-dihydroxyvitamin D.sub.3. Caverzacio et al., Endocrinol., 127: 453-459 [1990]. Further, a short term infusion of IGF-I alone into rats fasted for 60-72 hours was found to increase glomerular filtration rate (Hirschberg and Koppel, J. Clin. Invest., 83: 326-330 [1989]; see also Hirschberg et al., J. Clin. Invest., 87: 1200-1206 [1991]), and administration of IGF-I to humans was found to elevate glomerular filtration rate and renal plasma flow. Guler et al., Acta Endocrinol., 121: 101-106 (1989); Froesch et al., Trends in Endocrinology and Metabolism, p. 254-260 Vol. 1 Issue 5 (Elsevier Science Pub. Co., 1990). See also U.S. Pat. No. 5,106,832 issued 21 Apr. 1992.
In addition, EGF has been shown to accelerate the regeneration of renal repair in post-ischemic acute renal failure (Humes et al., J. Clin. Invest., 84: 1757-1761 [1989]; Norman et al., Clin. Sci., 78: 445-450 [1990]), and after damage with the nephrotoxin mercuric chloride. Coimbra et al., Am. J. Physiol., 259: F438 (1990). In addition, another growth factor, transforming growth factor-.alpha. (TGF-.alpha.) also has been reported to accelerate renal repair and recovery from ischemic injury to the kidney. Reiss et al., Kidney Internat., 37: 492 (i990).
Because administration of GH was found to increase glomerular filtration rate and renal plasma flow (Haffner et al., Clin. Nechrol., 32: 266-269 [1989]; Hirschberg et al., Kidney Int., 35: 865-870 [1989]), it has been suggested that this hormone could be used as a pharmacological agent to enhance renal function in the setting of chronic renal failure Gershberg, J. Clin. Endocrinol. Metab., 20: 1107-1119 (1960); White et al., Am. J. Physiol., 157: 47-51 (1949). However, in contrast to findings in the backdrop of normal renal function, administration of GH to human adults (Beck et al., Metabolism, 13: 1108-1134 [1964]; Haffner, supra) or children (Koch et al., J. Pediatr., 115: 365-371 [1989]) with chronic renal failure does not increase glomerular filtration rate. These studies employed subjects with chronic renal failure of varying severity and of many etiologies.
The acute role of IGF-I in the growth or repair of the kidney is more controversial. There are data showing that IGF-I protein is increased in kidneys undergoing hypertrophy due to GH treatment (D'Ercole et al., supra) or hypertrophy in the remaining kidney following unilateral nephrectomy (Stiles et al., supra), or following ischemic injury to the kidney (Andersson and Jennische, supra). Additionally, as of 1991 the role of IGF-I in renal compensatory hypertrophy was described as controversial. See Mulroney and Haramati, 73rd Annual Meeting, The Endocrine Society, Jun. 19-22, 1991, page 141 of Programs and Abstracts book, abstract 444. However, as IGF-I has many roles in the kidney, the elevation in tissue IGF-I content in these circumstances is not necessarily indicative of a role in the growth response of the kidney.
There is a major difference between the locality of IGF-I mRNA and IGF-I receptor mRNA. Message for IGF-I is found chiefly in collecting ducts "downstream" from the bulk of kidney IGF-I receptors, which are found mainly in the proximal tubules and are lacking in collecting ducts. Lajara et al., Am. J. Physiol., 257: F252-F261 (1989). This different distribution of receptors and ligand is unusual in that IGF-I receptors are found in the kidney cortex while IGF-I is found in the kidney medulla. It is possible that local renal IGF-I peptide has little activity in the kidney and that the IGF-I receptors in the tubules chiefly respond to endocrine IGF-I derived from the general circulation. The fundamental significance of changes in renal IGF-I (mRNA or peptide concentration), for example following renal damage, is therefore questionable. Also see Miller and Hammerman, Am. J. Physiol., F747-F751 (1990) and Martin et al., Proc. 2nd Int. IGF Symposium, p. 142 (1991).
Acute renal failure (ARF) complicates the course of nearly 5% of all hospitalized patients and 20% of intensive care unit patients. In 1% of all admissions renal failure is severe, increasing the overall risk of death six-fold. ARF is usually due to reduced renal blood flow caused by destruction of the proximal tubule or nephrotoxins leading to cell necrosis. This is followed by retention of nitrogenous products, fluids, and electrolytes and a state of accelerated catabolism. If the ARF is severe and prolonged, death occurs unless hemodialysis therapy is instituted. Current therapy includes early diagnosis and supportive care including fluid balance, electrolyte homeostasis, treatment of complicating medical problems, dialysis for any involved nephrotoxins, and careful monitoring. During this latter phase, which may last weeks, the patient is at high risk. There is a need in the art for a drug that will prevent ARF from occurring in the first instance or at least ameliorate its effects.
It is therefore an object of the present invention to provide a drug that is useful in preventing or ameliorating ARF in mammals that are at risk of suffering from ARF.
It is one specific object to prevent or ameliorate, most commonly, acute tubular necrosis leading to oliguria and azotermia, typically from an ischemic renal injury. Recovery from such moderate-severe injury typically requires in-patient dialysis, takes 4-6 weeks, and is associated with significant mortality.
It is another specific object to eliminate or decrease the need for dialysis in patients with ARF.
It is a further specific object to prevent or ameliorate nonoliguric renal failure.
These objects will be apparent to those of ordinary skill in the art.